Funding is requested for the acquisition of a liquid chromatography- tandem mass spectrometer (LC-MS-MS). Major users are from the departments of Chemistry (3), Biochemistry (2), and Biology (2), representing 9 NIH-funded projects. Minor users not funded by the NIH are from Chemistry (5), Biology (1) Biochemistry (2), and Entomology (2). Of the minor projects, two grant proposals are pending with the NIH and are likely to become major users. The LC-MS-MS is required for modern chemical biology, a rising field in biomedical research. A triple quadrupole MS-MS with an integrated capillary LC fulfills the requirements for the broad range of projects proposed to use the instrument, from natural product isolation, quantitation in metabolism studies and combinatorial chemistry for small molecules to sequencing of peptides and phosphoproteins in the macromolecular area. This instrument would have the unique capabilities of a triple quadrupole MS-MS at Virginia Tech. Prof. Castagnoli will discover and characterize neuroprotective and neurotoxic agents. Prof. Etzkorn will design and synthesize inhibitors of cell-cycle enzymes as potential anti- cancer agents. Prof. Kingston will elucidate the structures of natural products, design and synthesize derivatives of paclitaxel and study the mechanism of paclitaxel binding to tubulin and microtubules. Prof. Popham will characterize bacterial cell wall synthetic enzymes and analyze changes in wall structure. Prof. Carlier will design and synthesize bi- and multivalent probes of the GABA(A) receptor, and will use acetylcholinesterase to catalyze non-native chemical reactions. Prof. Taylor will demonstrate that supercritical fluid chromatography is a viable interface for mass spectral identification/quantification of drug- like materials. Prof. White will establish coenzyme biosynthetic intermediates in the Archaea. The instrument will be housed in a shared instrumentation laboratory located in the Chemistry Department and operated as a user-accessible, operator-maintained facility. The P.I., Felicia Etzkorn, in conjunction with Geno Iannaccone, Director of Analytical Services, is responsible for purchase, scientific and administrative oversight of the LC-MS-MS. User training, operation, maintenance and repair of the instrument will be the responsibility of the current mass spectrometrist, Ms. Anne Campbell.